tbuckley/cabot-search huggingface dataset:
Abstract 4105: Improvement of CD133-specific chimeric antigen receptor T cells by secreting anti-PD-L1 single-chain variable fragment against cholangiocarcinoma
Authors: Thanich Sangsuwannukul, Kamonlapat Supimon, Thaweesak Chieochansin, Kornkan Choomee, Jatuporn Sujjitjoon, Mutita Junking, Pa-thai Yenchitsomanus
Journal: Cancer Research (2023)

Abstract Cholangiocarcinoma (CCA) is rare but hard-to-treat solid cancer affecting people worldwide. Cancer stem cells (CSCs) in CCA contribute to tumor heterogeneity and resistance to conventional therapies. Thus, CSCs are notable targets for cancer immunotherapy. CD133 is a potential CSC surface marker overexpressed in various cancers. T cell-based immunotherapy, namely chimeric antigen receptor (CAR) T-cell targeting CD133 has shown potential in eradication of some solid tumors including CCA. Nevertheless, anti-tumor function of CAR T cell could be decreased under immunosuppressive tumor microenvironment (TME). Thus, to improve its function under TME, the next-generation of CD133-specific CAR T-cell is required. We therefore constructed two lentiviral vectors containing: (i) anti-CD133 single-chain variable fragment (scFv), 4-1BB costimulatory molecule, and CD3ζ (133CAR), and (ii) anti-CD133 scFv, 4-1BB, and CD3ζ in tandem with anti-PD-L1 scFv (133CARsL). The lentiviruses were transduced to generate CD133-specific CAR T cells expressing the second-generation (133CART) or anti-CD133 CAR with self-secreting anti-PD-L1 scFv (133CARTsL). The latter was able to simultaneously target CD133 and PD-L1 molecules on CCA cells. CCA cells endogenously expressing CD133 and PD-L1 were cocultured with either 133CART or 133CARTsL. In short-term coculture, the antitumor effects of 133CARTsL were not different from that of 133CART. However, in long-term coculture and after tumor re-challenge, 133CARTsL showed lower expression of programmed cell death protein (PD-1) and better cytotoxic function against high CD133 and PD-L1 CCA cells. The higher potential of 133CARTsL with reduced exhaustion profile would offer great promise for application of CD133-targeting CAR T cells in solid tumors. Citation Format: Thanich Sangsuwannukul, Kamonlapat Supimon, Thaweesak Chieochansin, Kornkan Choomee, Jatuporn Sujjitjoon, Mutita Junking, Pa-thai Yenchitsomanus. Improvement of CD133-specific chimeric antigen receptor T cells by secreting anti-PD-L1 single-chain variable fragment against cholangiocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4105.
Abstract 1596: The promising recipe sorafenib rosiglitazone and adipogenesis inducers cocktail for in vitro hepatocellular carcinoma differentiation induction besiege carcinogenesis
Authors: Aya Anis, Ahmed M. Mostafa, Nadia M. Hamdy, Ahmed S. Sultan
Journal: Cancer Research (2023)

Abstract Aim: The present study is focusing on using sorafenib, rosiglitazone, and adipogenesis-inducers cocktail (Insulin, Dexamethasone and IBMX) as a combination treatment to induce hepatocellular carcinoma (HCC) cell lines differentiation into adipocyte functioning cells, a strategy for effecting examined cancer cell lines to lose carcinogenicity properties and hopefully, turning into near-normal cells, with near-normal activity. The liver is one of the most vital organs in the body, any malfunctioning in the liver affects the whole body's health and performance. By 2040, 1.4 million people could be diagnosed with liver cancer and 1.3 million people could die from the disease, thus, trying an attempt to stop or reverse this cancer, would be a great break-through. Materials, Methods and Results: Using the current differentiation-induction cocktail to turn HepG2 and Hep3B HCC cancer cells into adipocytes, was confirmed by Oil Red O staining and morphological changes, and significantly expressed "adiponectin" level. Moreover, the cellular molecular markers p53, PPAR-γ, E-cadherin/β-catenin complex, and caspase-3 activities were significantly enhanced in the cocktail induced-differentiated cells, confirming the effectiveness of the proposed cocktail for ameliorating STAT3 together with inducing apoptosis (clonogenicity) , in comparison to control cells or HCC cells treated with the cocktail individual drugs. The differentiation-induction cocktail through rosiglitazone activated PPAR-γ which in turn increased HCC cells sensitivity to insulin to induce lipid uptake. Sorafenib, in the cocktail, role to block tumor cell proliferation via inhibiting STAT3 signaling pathway activation. In conclusion, the current proposed differentiation-induction cocktail after further in vivo confirmation (future prospective) might open a different avenue for liver cancer treatment. Citation Format: Aya Anis, Ahmed M. Mostafa, Nadia M. Hamdy, Ahmed S. Sultan. The promising recipe sorafenib rosiglitazone and adipogenesis inducers cocktail for in vitro hepatocellular carcinoma differentiation induction besiege carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1596.
Abstract 5767: Pan-viral response in African Americans and European Americans with hepatocellular carcinoma
Authors: Theressa Ewa, Whitney L. Do, Limin Wang, Marshonna Forgues, Xin W. Wang
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC) is often diagnosed at late-stages, with African Americans (AA) being diagnosed at a later stage with worse prognosis and high mortality rates. The poor screening and diagnosis of HCC and differences between racial/ethnic groups show a disproportion in mortality rates. Examining an individual’s viral exposure history might serve as a useful biomarker of early disease that could address and, potentially, alleviate this disparity. We aim to investigate whether viral features can be used to identify HCC and individuals at high risk (HR) of HCC. Additionally, we examine the racial/ethnic differences in viral exposures and whether viral exposure history accounts for epidemiological disparity described previously. Herein we use a technique called VirScan, which conjugates Phage Immunoprecipitation sequencing (PhIP-seq) and DNA sequencing, to profile an individual’s epitope antibody repertoire upon viral exposure. We performed VirScan on serum and plasma samples from 199 AA (130 HR and 79 HCC) and 260 European Americans (EA) (210 HR and 50 HCC) participants from the NCI-UMD cohort (NCT00913757; clinicaltrials.gov). We used a machine-learning XGBoost model to classify viral features that can discriminate HCC or HR. A composite viral score was generated using the SHAP value of the most significant viral features from the model with a higher score more predictive of HCC. Secondary analyses using Wilcoxon-Rank sums tests and Cox proportional hazard analysis revealed that while race/ethnicity did not differentially predict HCC in this cohort, the viral score was significantly higher in AA compared to EA in the HR group (p = 0.027). XGBoost search identified 235 important viral features which distinguish HCC from HR. Out of the 235 viral features, 20 viruses were different between AA and EA (FDR &amp;lt; 0.05). We also found the viral score was positively associated with incident mortality in HCC group over the study period of 8 years (p=0.03). Thus, we demonstrate that the viral history of an individual might be useful in early detection of HCC. This approach could be used to account for the disparities we see in both incidence and mortality of HCC between AA and EA. Citation Format: Theressa Ewa, Whitney L. Do, Limin Wang, Marshonna Forgues, Xin W. Wang. Pan-viral response in African Americans and European Americans with hepatocellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5767.
Abstract 3018: Demographic and social patterns of average values of inflammatorymarkers in US adults: A 2009-2016 NHANES analysis
Authors: Marlene Camacho-Rivera, Zachary Ye, Raisa Haq, Rose Calixte
Journal: Cancer Research (2023)

Abstract Several studies report the negative impact of elevated Neutrophil-to-Lymphocyte ratio (NLR) and elevated Platelet-to-Lymphocyte ratio (PLR) on outcomes in many surgical and medical conditions, including cancer. In order to use these inflammatory biomarkers as prognostic factors in disease, a normal value in disease-free individuals must be identified first. This study aims to (1) establish average values of various inflammatory markers using a healthy and nationally representative U.S. adult population and (2) explore heterogeneity in average values by sociodemographic and behavioral risk factors to better specify cut-off points accordingly. The National Health and Nutrition Examination Survey (NHANES) of aggregated cross-sectional data collected from 2009 to 2016 was analyzed; data extracted included markers of systemic inflammation and demographic variables. We excluded participants who were under 20 or had a history of inflammatory diseases such as arthritis and gout. Adjusted linear regression models were used to examine the association between demographic and behavioral characteristics and neutrophil counts, platelet counts, lymphocyte counts, NLR, and PLR. The average NLR is 2.16 and the average PLR is 121.31. Non-Hispanic Black participants have significantly lower mean NLR values (1.78, 95% CI 1.74–1.83 and 2.10, 95% CI 2.04–2.16 respectively) when compared to non-Hispanic Whites (2.27, 95% CI 2.22–2.30–p&amp;lt;0.0001). Participants who reported any no smoking history had significantly lower NLR than subjects who reported any smoking history and higher PLR than current smokers. The average PLR for non-Hispanic blacks is significantly lower compared to non-Hispanic whites. Participants ages 20-29 have significantly lower mean PLR vs. participants in the age groups 30-59, 60-79, and 80 and older. Additionally, current smokers have significantly higher mean PLR compared to those who never smoke. Participants in the obese category also had higher mean PLR compared to normal weight participants. This study provides nationally representative estimates for demographic and behavioral effects on NLR, and PLR, which have been associated with several chronic disease outcomes, suggesting that different cut-off points for inflammatory markers should be set according to social factors. Citation Format: Marlene Camacho-Rivera, Zachary Ye, Raisa Haq, Rose Calixte. Demographic and social patterns of average values of inflammatorymarkers in US adults: A 2009-2016 NHANES analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3018.
Abstract 4816: Targeting GCN2 regulation of amino acid homeostasis sensitizes prostate cancer cells to senolytic therapies
Authors: Noah R. Sommers, Ricardo A. Cordova, Angela J. Klunk, Roberto Pili, Ronald C. Wek, Kirk A. Staschke
Journal: Cancer Research (2023)

Abstract The integrated stress response (ISR) features a family of eIF2 kinases that sense cellular stress, triggering translational and transcriptional modes of gene expression that enhance cell adaptation to the underlying stress. Previously we reported (Cordova et al., 2022 eLife) that prostate cancer (PCa) cells rely on one of these eIF2 kinases, GCN2, for maintenance of amino acid homeostasis and sustained proliferation. GCN2 functions to enhance expression of amino acid transporters and subsequent import of essential amino acids (EAAs) that are necessary to sustain PCa growth. Genetic loss or pharmacological inhibition of GCN2 results in decreased expression of amino acid transporters, severe depletion of intracellular EAAs, and decreased proliferation of PCa cells in culture and mouse xenograft models. Although loss of GCN2 in PCa cells reduces proliferation, depletion of this eIF2 kinase is suggested to lead to cell stasis and modest cell death. We hypothesize that the static phenotype by GCN2 inhibition in PCa cells renders these cells vulnerable to senolytic treatment and is a potential therapeutic target in combination therapies. To address this idea, we utilized models of androgen-sensitive and castration-resistant PCa and non-tumorigenic prostate epithelial cells. GCN2 inhibition induced a static phenotype in PCa cell lines, but not non-tumorigenic prostate epithelial cells, and this was accompanied by increased expression of the senescent markers p53, p21, p27, and MCL-1. Furthermore, induction of senescent markers following GCN2 inhibition in PCa cells was reversed by supplementation with EAAs, suggesting that limitation of EAAs is critical to the induction of cell stasis. Of importance, treatment of PCa cells with Navitoclax, a senolytic agent that targets Bcl-2 family of anti-apoptotic proteins, in combination with GCN2 inhibition resulted in enhanced cell death and apoptosis compared to each single treatment alone. Our results suggest that GCN2 inhibition in PCa cells leads to depletion of EAAs and induction of a static phenotype, rendering these cells vulnerable to targeting the Bcl-2 family of proteins to expedite cell death. As such, therapies integrating GCN2 inhibition and senolytic agents are proposed to be effective strategies for treatment of PCa. Citation Format: Noah R. Sommers, Ricardo A. Cordova, Angela J. Klunk, Roberto Pili, Ronald C. Wek, Kirk A. Staschke. Targeting GCN2 regulation of amino acid homeostasis sensitizes prostate cancer cells to senolytic therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4816.
Abstract 1935: Racial and ethnic disparities in survival among women with advanced-stage ovarian cancer who received systemic therapy: A National Cancer Database analysis
Authors: Caretia J. Washington, Shama D. Karanth, Dejana Braithwaite, Tomi F. Akinyemiju
Journal: Cancer Research (2023)

Abstract Purpose: To evaluate the association between race and ethnicity and all-cause mortality among women with advanced-stage ovarian cancer who received systemic therapy. Methods: We obtained data from the National Cancer Database on women diagnosed with advanced-stage ovarian cancer from 2004 to 2015. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) by race and ethnicity groups (non-Hispanic (NH)-White, NH-Black, Hispanic, NH-Asian/Pacific Islander, and Other) and to examine the association of race/ethnicity with survival, stratified by age and comorbidity while adjusting for clinical and demographic variables. Results: There were 53,367 women (52.4% ages ≥ 65 years, 8.7% NH-Black, 5.7% Hispanic, and 2.7% NH-Asian/Pacific Islander) included in the analysis. NH-Black women had a higher risk of death compared to NH-White women (HR: 1.13; 95% CI: 1.07,1.18), while Hispanic women had a lower risk of death compared to NH-White women (HR: 0.89; 95% CI: 0.82,0.97). The Black-White disparity persisted for women ages &amp;lt; 65 years and ≥ 65 years, and among women with no comorbidities (HR:1.14; 95% CI: 1.08,1.21). Conclusion: Among women with advanced-stage ovarian cancer who received systemic therapy, NH-Black women experienced decreased survival compared with NH-White women, regardless of age and comorbidity status. Additional research is essential to identify drivers of ovarian cancer disparities, including racial differences in treatment response. Citation Format: Caretia J. Washington, Shama D. Karanth, Dejana Braithwaite, Tomi F. Akinyemiju. Racial and ethnic disparities in survival among women with advanced-stage ovarian cancer who received systemic therapy: A National Cancer Database analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1935.
Abstract 4015: EGFR activation via c-Jun axis promotes adaptive resistance to third generation ALK-TKI lorlatinib in ALK-rearranged non-small cell lung cancer cells
Authors: Yuki Katayama, Tadaaki Yamada, Kenji Morimoto, Hiroaki Ozasa, Shinsaku Tokuda, Koichi Takayama
Journal: Cancer Research (2023)

Abstract Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including lorlatinib have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare, as a small population of tumor cells survives due to adaptive resistance. In this preclinical study, we investigated the adaptive resistant mechanisms to lorlatinib and its therapeutic strategies to overcome, using in vitro and in vivo experiments. We have identified EGFR as an adaptive resistance mechanism of lorlatinib using phospho-RTK array and siRNA library. Cell line-based assay showed that exposure of lorlatinib accelerated EGFR signal activation as an adaptive response via activation of JNK cascade in ALK-rearranged lung cancer cells. Knockdown for EGFR suppressed the survival signal of ALK lung cancer cells when treated with lorlatinib. The combination of lorlatinib and erlotinib, a first-generation EGFR-TKI, was shown to enhance cell growth inhibition by inducing cell apoptosis via suppressing the anti-apoptotic factor Bcl-xl compared with lorlatinib monotherapy. Moreover, cell line-derived xenograft model indicated that the combination of lorlatinib plus erlotinib enhanced anti-tumor effects compared with lorlatinib monotherapy. Taken together, our results displayed that EGFR activation plays an important role in the initial adaptive resistance to lorlatinib for ALK-rearranged lung cancer. The combination of lorlatinib and erlotinib is expected as the promising strategy for those tumors. Citation Format: Yuki Katayama, Tadaaki Yamada, Kenji Morimoto, Hiroaki Ozasa, Shinsaku Tokuda, Koichi Takayama. EGFR activation via c-Jun axis promotes adaptive resistance to third generation ALK-TKI lorlatinib in ALK-rearranged non-small cell lung cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4015.
Abstract 707: High major histocompatibility complex class I expression overcomes cancer immunotherapy resistance due to interferon gamma signaling pathway defects
Authors: Katsushige Kawase, Shusuke Kawashima, Joji Nagasaki, Takashi Inozume, Hiromasa Yamamoto, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi
Journal: Cancer Research (2023)

Abstract IFN-γ signaling pathway defects such as JAK mutations are well-known mechanisms of resistance to immune checkpoint inhibitors (ICIs). However, some patients respond to ICIs despite IFN-γ signaling pathway defects, and the detailed mechanisms remain unclear. Here, we created JAK-deleted cancer cell lines and evaluated antitumor immunity. As a result, several tumors responded to PD-1 blockade despite JAK deletion. Such sensitive tumors had high major histocompatibility complex class I (MHC-I) expression despite IFN-γ signaling pathway defects, whereas MHC-I expression was reduced by JAK deletion in resistant tumors. In particular, if cancer cells had high MHC-I expression despite defects in IFN-γ signaling pathways, chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment. Accordingly, we found a response to ICIs in a patient with JAK-negative head and neck squamous cell carcinoma, whose human leukocyte antigen class I (HLA-I) expression level was maintained. In addition, clustered regularly interspaced short palindromic repeats (CRISPR) screening to identify molecules with elevated MHC-I expression independent of IFN-γ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFN-ɤ signaling pathway defects are not always resistant to ICIs, and highlight the importance of MHC-I expression among the pathways, including inhibitory effects on cellular proliferation or chemokine production, and the possibility of NF-κB-targeted therapies to overcome such resistance. Citation Format: Katsushige Kawase, Shusuke Kawashima, Joji Nagasaki, Takashi Inozume, Hiromasa Yamamoto, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi. High major histocompatibility complex class I expression overcomes cancer immunotherapy resistance due to interferon gamma signaling pathway defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 707.
Abstract 700: Induction of cancer-specific T-cell responses in patients immunized with P10s-PADRE vaccine
Authors: John J. Lee, Bernice C. Nounamo, Fariba Jousheghany, Issam Makhoul, Eric R. Siegel, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi
Journal: Cancer Research (2023)

Abstract Introduction: HR+/HER2− breast cancer is the most common form of breast cancer in the United States. HR+/HER2− tumors are known for a low number of tumor-infiltrating lymphocytes (TILs) and considered less immunogenic than other breast cancer subtypes. We have demonstrated that vaccination with P10s-PADRE, a carbohydrate-mimetic-based peptide, cancer vaccine in combination with standard-of-care chemotherapy in HR+/HER2− breast cancer patients led to an increase in TILs and stromal CD3+ T cells. The current study was performed to determine the vaccine specificity and anti-tumor functionality of T cells in treated patients. Methods: Peripheral blood mononuclear cells (PBMCs) collected at the baseline and after vaccination were used in T-cell assays by multi-color ELISpot, examining Th1, Th2, and cytotoxic responses. PBMCs were also interrogated for the vaccine-induced changes in immune gene expression by next-generation RNA-seq analysis. Results: We observed a significant increase in IFN-g, but not in IL-5 or IL-10, responses in post-immune PBMCs after stimulation with P10s, P10s-PADRE and polyclonal stimulation of T cells by anti-CD3/CD28 antibodies. Stimulation with cancer cell lysate resulted in a strikingly high IFN-g response in post-immune samples. Determining the trio of IFN-g, GzB, and IL-2 together with CD4/CD8 cell proliferation assays of consequent post vaccination specimens established the dynamics of effector T-cell populations. RNA-seq data clearly distinguished post-treatment samples by the increase in immune cell activation, cytokine response, and antigen presentation. Conclusions: The data indicate that immunization of HR+/HER2− breast cancer patients with P10s-PADRE in combination with chemotherapy leads to specific activation of T-cells that recognize breast cancer cells. Improving immunogenicity of such immunologically cold tumors could increase the effectiveness of standard therapeutic approaches. Citation Format: John J. Lee, Bernice C. Nounamo, Fariba Jousheghany, Issam Makhoul, Eric R. Siegel, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi. Induction of cancer-specific T-cell responses in patients immunized with P10s-PADRE vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 700.